The present invention relates to controlled release pharmaceutical compositions. More specifically, this invention is directed to compositions which include a solution or suspension vehicle and a pharmaceutically active agent which can be administered to the body in a normally liquid formulation and thereafter form a semi-solid or gel-like matrix in the environment of the stomach thereby effecting controlled release of the incorporated medicament.
Since the salient aspect of drug delivery by familiar conventional dosage forms, including tablets, capsules, eye drops and injectors is the fluctuation between high and low concentration within each interval between dosing, the pharmaceutical industry has directed much of its developmental effort to prolonging the residence time of drug molecules in the body to enhance convenience of the regimen and improve patient compliance. Moreover, certain medicants, particularly those exhibiting a short half-life which necessitate frequent dosing, are too rapidly absorbed and sometimes result in peak serum levels that are excessively high. Such circumstances often result in the development of toxic symptoms.
Thus, it is known in the pharmaceutical arts to prepare pharmaceutical compositions which may be administered by various methods, e.g., orally, topically, rectally, opthalmicly, oticly, etc. to humans and animals which provide for a delayed release of the active ingredient incorporated in the particular composition. In all of these methods the purpose and effect are the same, i.e., to provide more precise control over drug concentration in the blood or target tissue and prolonged drug activity while avoiding symptomatic side effects. Ideally, by releasing a drug in vivo according to a predictable, therapeutically rational rate or rate program, such pharmaceuticals deliver drugs systemically or to a particular target organ continuously for a specified length of time thereby programming any desired time pattern of drug release and permitting delivery at a constant rate, i.e., a rate equal to the rate of loss.
The ability to control the duration of drug release and to maintain the drug at a predictable, specified concentration in vivo offers many advantages over other forms of medication. For example, less total drug may suffice for treatment than with conventional dosage thereby eliminating harmful side effects. Such deleterious side effects may specifically include gastric irritation and erosion, e.g., the gastrointestinal bleeding that occurs with long term use of conventional forms of aspirin declines when it is administered in controlled-release form.
Several slow release formulations are well known in the art including enteric coated pellets, tablets and capsules and/or formulations wherein the active ingredients are dispersed in a medium totally insoluble in physiologic fluids or wherein the release of the active medicament is brought about by a breakdown of formulations due to mechanical means. For example, U.S. Pat. No. 4,292,299 to Suzuki, et al. discloses a slow-releasing medical preparation which is administered by adhering to the wet mucous surface of a mucous membrane and skin of humans or animals. The composition includes an adhesive polymer which swells upon moistening and a non-adhesive layer which contains the particular medicament. U.S. Pat. No. 4,235,870 to Leslie describes slow-release compositions which include a higher aliphatic alcohol in combination with certain hydrated materials such as hydrated hydroxy-alkyl cellulose in critical proportion which thereby achieves delayed and uniform release of the medicament incorporated in the composition. U.S. Pat. No. 3,493,652 to Hartman relates to a method of effecting the controlled release of pharmaceutical dosage by the coordination of enzyme activity on a particular substrate material contained in the composition.